This proposal represents a highly innovative and perhaps unique approach to lay the foundation for understanding the pathogenesis of COVID19-driven pathologies in man. Here we bring three distinct scientific approaches together in a novel and coordinated fashion to analyze key steps in innate immune response to COVID-19 infection. The fundamental studies of the NLRP3 inflammasome pathway is both deep and broad given the nearly 20-year experience of the Ulevitch lab in studying various members of the NLR family at the level of pathway analysis. While drawing on information from studies in murine cells (genetic, biochemical and cell biologic) the focus here is on human M? where the Ulevitch lab has built a broad approach with immunologic, cell biologic and genetic approaches. The Nolan lab has pioneered the use of high content imaging approaches for analyzing cells and tissues. The high parameter technologies maximize the breadth of immune features analyzed in samples for rapid discovery. CyTOF gives 42-channel info for millions of cells in blood. CODEX spatially resolves single cells in tissues with >60 parameters, while ViralMIBI brings viral nucleic acid detection to antibody-based multiparameter imaging defining cellular niches of infection. Combining these technologies with SARS-CoV2 challenge models and the Collaborative Cross will also result in the identification of mouse models that most closely match the disease phenotypes and molecular signatures of COVID-19 disease in humans. If deemed useful we can also use information and/or murine strains derived from forward genetic efforts in the Beutler lab. The latter has been an integral part of the Scripps U19 program since the initial funding in 2001/2002.